SOLID FORMS OF (4-(2-FLUORO-4-(1-METHYL-1H-BENZO[d]IMIDAZOL-5-YL)BENZOYL) PIPERAZINE-1-YL)(1-HYDROXYCYCLOPROPYL)METHANONE

ABSTRACT

The present disclosure reports solid forms of (4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone:

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 16/667,602, filed Oct. 29, 2019, which claims the benefit of U.S. Provisional Application No. 62/752,229, filed Oct. 29, 2018, both of which are incorporated by reference in their entirety.

TECHNICAL FIELD

The present disclosure relates to pharmaceutical compositions, including solid forms of a certain compound useful for inhibiting fatty acid synthase (FASN).

BACKGROUND

Chemical compounds can form one or more different pharmaceutically acceptable solid forms, such as various polymorph crystal forms. Individual solid forms of bioactive chemical compounds can have different properties. There is a need for the identification and selection of appropriate solid forms of bioactive chemical compounds (including appropriate crystalline forms, where applicable) for the development of pharmaceutically acceptable dosage forms for the treatment of various diseases or conditions.

The compound, (4-(2-fluoro-4-(1-methyl-H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (Compound 1), is a small molecule inhibitor of fatty acid synthase (FASN):

Compound 1 is disclosed in PCT Application Publication No. WO 2014/164749 as one of many compounds suitable as small molecule inhibitors of FASN.

Therapeutic compounds often exist in a variety of solid forms having different properties. There remains a need for identifying solid forms of Compound 1 useful for various therapeutic applications.

SUMMARY

Novel solid forms of Compound 1 disclosed herein include Form B, Form C, and Form X, as well as compositions comprising a solid form of Compound 1 comprising one or more of Form B, Form C, Form X and Form Z. In addition, a novel mixture of solid forms of Compound 1, Mixture A, is disclosed herein, as well as compositions comprising Mixture A.

A novel Compound 1 Mixture A can be identified by X-ray Powder Diffraction (XRPD), having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3. A novel Compound 1 Mixture A can be identified by XRPD having characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3, and not having a characteristic diffraction at angle (2 theta±0.2) of 24.2. A novel Compound 1 Mixture A can be identified (i) by differential scanning calorimetry (DSC) having two endotherms at 226.2° C. and 229.1° C.; and (ii) by XRPD having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3.

A novel Compound 1 Form B can be identified by XRPD, having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3. A novel Compound 1 Form B can be identified by XRPD, having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3, and not having one or more characteristic diffractions at angles (2 theta±0.2) of 7.2, 8.4, 14.9, 16.1, and 17.8 and/or not having a characteristic diffraction at angle (2 theta±0.2) of 24.2. A novel Compound 1 Form B can be identified (i) by DSC having one endotherm at 225.7° C.; and (ii) by XRPD having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3.

A novel Compound 1 Form C can be identified by XRPD, having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, 22.2, and 26.6.

A novel Compound 1 Form X can be identified by XRPD, having one or more characteristic diffractions at angles (2 theta±0.2) of 7.2, 8.4, 14.9, 16.1, and 17.8.

A novel Compound Form Z can be identified by XRPD, having characteristic diffraction at angles (2 theta) as exemplified in FIG. 11.

The Applicant has also discovered that novel Compound 1 solid forms or solid form mixtures (e.g., Form B, Form C, Form X, and Mixture A) can also be obtained by subjecting or maintaining a Compound 1 solid form under physical conditions effective to convert Compound 1 as a first solid form into Compound 1 as a second solid form.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an XRPD pattern of Compound 1 Mixture A.

FIG. 2 is a thermogravimetric analysis (TGA) curve (upper curve) and a DSC thermogram (lower curve) for Compound 1 Mixture A.

FIG. 3 depicts an XRPD pattern of Compound 1 Form B.

FIG. 4 is a TGA curve (upper curve) and a DSC thermogram (lower curve) for Compound 1 Form B.

FIG. 5 depicts a Dynamic Vapor Sorption (DVS) plot of Compound 1 Form B.

FIG. 6 depicts a series of XRPD patterns of Compound 1 Form B before and after DVS analysis.

FIG. 7 depicts an XRPD pattern of Compound 1 Form C.

FIG. 8 is a TGA curve (upper curve) and a DSC thermogram (lower curve) for Compound 1 Form C.

FIG. 9 depicts an XRPD pattern of Compound 1 Form X.

FIG. 10 is a TGA curve (upper curve) and a DSC thermogram (lower curve) for Compound 1 Form X.

FIG. 11 depicts an XRPD pattern of Compound 1 Form Z, along with a reference pattern of Compound 1 Mixture A.

FIG. 12 is a DSC thermogram for Compound 1 Form Z.

FIG. 13 depicts a series of XRPD patterns from the results of a stability evaluation of Compound 1 Mixture A, Form B, and Form X.

FIG. 14 depicts a series of XRPD patterns from the results of a stability evaluation of Compound 1 Form B and Form C.

FIG. 15 depicts a series of XRPD patterns from the results of a phase stability evaluation of Compound 1 Form B.

DETAILED DESCRIPTION

The present disclosure provides novel Compound 1 solid forms and mixtures thereof, pharmaceutical compositions thereof, methods of preparation thereof, and methods of use thereof. Compound 1 is the FASN inhibitor bioactive compound (4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (Compound 1), can be prepared as one or more solid forms. The chemical structure of Compound 1 is shown below:

Compound 1 can occur in an amorphous solid form or in a crystalline solid form or in mixtures of solid forms. Crystalline solid forms of Compound 1 can exist in one or more unique solid forms, which can additionally comprise one or more equivalents of water or solvent (i.e., hydrates or solvates, respectively). Accordingly, in some embodiments, the present disclosure provides a crystalline solid form of Compound 1. Crystalline forms of Compound 1 disclosed herein have distinct characteristics (e.g., characteristic XRPD peaks disclosed herein). Novel Compound 1 solid forms or solid form mixtures can be obtained by methods reported in the Examples (e.g., Example 2). Different methods of preparation can lead to different solid forms or solid form mixtures. For example, Compound 1 Form B can be obtained from a slurry comprising Compound 1 in ethanol at 50° C., as described in Example 2.

In some embodiments, certain solid forms or solid form mixtures of Compound 1 can be converted from one solid form to another solid form. For example, subjecting Compound 1 Mixture A and/or Form C to certain conditions yields at least Form B. Conditions suitable for converting Mixture A and/or Form C to Form B include conditions such as slurrying at room temperature, slurrying at 50° C., slurrying at 80° C., slurrying at reflux, and recrystallization.

Certain solid forms or solid form mixtures of Compound 1 can be prepared by forming a suspension (i.e., “slurrying”) comprising Compound 1 Mixture A and/or Form C and a solvent, and maintaining the suspension for a period of time sufficient to generate certain solid forms of Compound 1 (e.g., Form B). Exemplary solvents suitable to generate Form B include ethyl acetate (EtOAc), acetonitrile (ACN), heptane, isopropyl alcohol (IPA), and ethanol (EtOH). In some embodiments, a solvent is EtOAc. In some embodiments, a solvent is ACN. In some embodiments, a solvent is heptane. In some embodiments, a solvent is IPA. In some embodiments, a solvent is EtOH. In some embodiments, the suspension is maintained at room temperature. In some embodiments, the suspension is heated to a temperature between about 40° C. and 110° C. In some embodiments, the suspension is heated to a temperature of about 50° C. In some embodiments, the suspension is heated to a temperature of about 80° C. In some embodiments, the suspension is heated to a temperature of about 100° C. In some embodiments, the suspension is heated to reflux.

Certain solid forms or solid form mixtures of Compound 1 can be prepared by forming a suspension (i.e., “slurrying”) comprising Compound 1 Mixture A, Form C, and/or Form X and a solvent, and maintaining the suspension for a period of time sufficient to generate certain solid forms of Compound 1 (e.g., Form B). Exemplary solvents suitable to generate Form B include ethyl acetate (EtOAc), acetonitrile (ACN), heptane, isopropyl alcohol (IPA), and ethanol (EtOH). In some embodiments, a solvent is EtOAc. In some embodiments, a solvent is ACN. In some embodiments, a solvent is heptane. In some embodiments, a solvent is IPA. In some embodiments, a solvent is EtOH. In some embodiments, the suspension is maintained at room temperature. In some embodiments, the suspension is heated to a temperature between about 40° C. and 110° C. In some embodiments, the suspension is heated to a temperature of about 50° C. In some embodiments, the suspension is heated to a temperature of about 80° C. In some embodiments, the suspension is heated to a temperature of about 100° C. In some embodiments, the suspension is heated to reflux. In some embodiments, the disclosure relates to a solid form of Compound 1 that would be obtained by the foregoing process (or any embodiment thereof). In such embodiments, the solid form need not be prepared by such process, so long as the solid form is the same as the solid form that would be obtained by such process.

In some embodiments, certain solid forms of Compound 1 can be prepared by forming a salt of Compound 1, neutralizing said salt of Compound 1, and then allowing certain solid forms of Compound 1 (e.g., Form X) to precipitate from solution. For example, protonation of Compound 1 Form B with HCl in acetonitrile, followed by neutralization with NaOH (aq), and allowing precipitation at room temperature generates Compound 1 Form X.

In some embodiments, a solid form mixture of Compound 1 (e.g., Mixture A) is a mixture of two solid forms (e.g., Form B and another solid form). In some embodiments, a solid form mixture of Compound 1 (e.g., Mixture A) comprises two solid forms (e.g., Form B and another solid form).

The solid forms of Compound 1 disclosed herein include Compound 1 Form B, Form C, and Form X, as well as compositions comprising a solid form of Compound 1 comprising one or more of Form B, Form C, and Form X. The solid form mixtures of Compound 1 disclosed herein include Compound 1 in Mixture A, as well as compositions comprising a solid form mixture of Compound 1, comprising Mixture A. The solid forms and solid form mixtures of Compound 1 can be identified by various analytical techniques, such as XRPD and DSC.

A novel Compound 1 Mixture A can be identified by XRPD, having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3. A novel Compound 1 Mixture A can be identified by XRPD having characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3, and not having a diffraction at angle (2 theta±0.2) of 24.2. In some embodiments, Compound 1 Mixture A can be identified by XRPD, having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, 21.0, and 22.3. In some embodiments, Compound 1 Mixture A can be identified by XRPD, having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3, corresponding to d-spacing (angstroms±0.2) of 9.3, 8.7, 5.7, 4.5, and 4.0, respectively.

In some embodiments, Compound 1 Mixture A is characterized by an XPRD having one or more peaks at substantially the same angles (2 theta±0.2) of:

-   -   7.9     -   9.6     -   10.1     -   10.7     -   12.6     -   13.4     -   13.9     -   14.3     -   15.4     -   16.3     -   16.8     -   17.4     -   18.5     -   19.6     -   20.2     -   21.0     -   21.4     -   22.1     -   22.2     -   23.4     -   23.8     -   25.0     -   25.3     -   26.5     -   26.8     -   27.2     -   28.0     -   29.0     -   29.4     -   30.5     -   31.1     -   31.8     -   32.9     -   33.6     -   34.1     -   37.3     -   37.9.

In some embodiments, Compound 1 Mixture A is characterized by an XRPD having one or more peaks at substantially the same angles (2 theta±0.2), corresponding to d-spacing (angstroms±0.2) of:

2 Theta d-spacing (Å) 7.9 11.1 9.6 9.3 10.1 8.7 10.7 8.3 12.6 7.0 13.4 6.6 13.9 6.4 14.3 6.2 15.4 5.7 16.3 5.4 16.8 5.3 17.4 5.1 18.5 4.8 19.6 4.5 20.2 4.4 21.0 4.2 21.4 4.2 22.1 4.0 22.2 4.0 23.4 3.8 23.8 3.7 25.0 3.6 25.3 3.5 26.5 3.4 26.8 3.3 27.2 3.3 28.0 3.2 29.0 3.1 29.4 3.0 30.5 2.9 31.1 2.9 31.8 2.8 32.9 2.7 33.6 2.7 34.1 2.6 37.3 2.4 37.9 2.4.

A novel Compound 1 Mixture A can be identified by DSC, having two endotherms at 226.2° C. and 229.1° C. In some embodiments, Compound 1 Mixture A can be identified (i) by DSC having two endotherms at 226.2° C. and 229.1° C.; and (ii) by XRPD having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3. In some embodiments, Compound 1 Mixture A can be identified (i) by DSC having two endotherms at 226.2° C. and 229.1° C.; (ii) by XRPD having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3; and (iii) by XRPD not having a characteristic diffraction at an angle (2 theta±0.2) of 24.2.

A novel Compound 1 Form B can be identified by XRPD, having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3. In some embodiments, Compound 1 Form B can be identified by XRPD, having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3, corresponding to d-spacing (angstroms±0.2) of 9.2, 8.7, 5.7, 4.5, and 4.0. In some embodiments, Compound 1 Form B can be identified by XRPD, (i) having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3, and (ii) not having a characteristic diffraction at an angle (2 theta±0.2) of 24.2. In some embodiments, Compound 1 Form B can be identified by XRPD, (i) having one or more characteristic diffractions at angles (2 theta±0.2) of 15.4, 19.6, and 22.3, and (ii) not having a characteristic diffraction at an angle (2 theta±0.2) of 24.2. In some embodiments, Compound 1 Form B can be identified by XRPD, (i) having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3, and (ii) not having one or more characteristic diffractions at angles (2 theta±0.2) of 7.2, 8.5, 14.9, 16.1, and 17.8. In some embodiments, Compound 1 Form B can be identified by XRPD, (i) having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3; (ii) not having a characteristic diffraction at an angle (2 theta±0.2) of 24.2; and (iii) not having one or more characteristic diffractions at angles (2 theta±0.2) of 7.2, 8.5, 14.9, 16.1, and 17.8.

In some embodiments, Compound 1 Form B is characterized by an XRPD having one or more peaks at substantially the same angles (2 theta±0.2) of:

-   -   9.6     -   10.1     -   10.7     -   12.6     -   13.9     -   14.3     -   15.4     -   16.4     -   16.6     -   17.4     -   18.2     -   18.5     -   19.6     -   20.2     -   22.1     -   22.3     -   23.4     -   23.8     -   25.0     -   25.3     -   26.5     -   26.9     -   28.0     -   29.0     -   29.5     -   30.5     -   31.1     -   31.8     -   32.9     -   34.1     -   37.3     -   37.9.

In some embodiments, Compound 1 Form B is characterized by an XRPD having one or more peaks at substantially the same angles (2 theta±0.2), corresponding to d-spacing (angstroms±0.2) of:

2 Theta d-spacing (Å) 9.6 9.2 10.1 8.7 10.7 8.3 12.6 7.0 13.9 6.4 14.3 6.2 15.4 5.7 16.4 5.4 16.6 5.3 17.4 5.1 18.2 4.9 18.5 4.8 19.6 4.5 20.2 4.4 22.1 4.0 22.3 4.0 23.4 3.8 23.8 3.7 25.0 3.6 25.3 3.5 26.5 3.4 26.9 3.3 28.0 3.2 29.0 3.1 29.5 3.0 30.5 2.9 31.1 2.9 31.8 2.8 32.9 2.7 34.1 2.6 37.3 2.4 37.9 2.4.

A novel Compound 1 Form B can be identified by DSC, having one endotherm at 225.7° C. In some embodiments, Compound 1 Form B can be identified (i) by DSC having one endotherm at 225.7° C.; and (ii) by XRPD having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3. In some embodiments, Compound 1 Form B can be identified (i) by DSC having one endotherm at 225.7° C.; (ii) by XRPD having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3; and (iii) by XRPD not having one or more characteristic diffractions at angles (2 theta±0.2) of 7.2, 8.5, 14.9, 16.1, and 17.8. In some embodiments, Compound 1 Form B can be identified (i) by DSC having one endotherm at 225.7° C.; (ii) by XRPD having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3; and (iii) by XRPD not having a characteristic diffraction at angle (2 theta±0.2) of 24.2. In some embodiments, Compound 1 Form B can be identified (i) by DSC having one endotherm at 225.7° C.; (ii) by XRPD having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3; and (iii) by XRPD not having one or more characteristic diffractions at angles (2 theta±0.2) of 7.2, 8.5, 14.9, 16.1, 17.8, and 24.2. In some embodiments, Compound 1 Form B is substantially free of Form C and Form X.

A novel Compound 1 Form C can be identified by XRPD, having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 15.4, 19.6, 22.3, and 26.6. In some embodiments, Compound 1 Form C can be identified by XRPD, having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 15.4, 19.6, 22.3, 24.2, and 26.6. In some embodiments, Compound 1 Form C can be identified by XRPD, having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 15.4, 19.6, 22.3, and 26.6, corresponding to d-spacing (angstroms±0.2) of 9.3, 5.7, 4.5, 4.0, and 3.3.

In some embodiments, Compound 1 Form C is characterized by an XRPD having one or more peaks at substantially the same angles (2 theta±0.2) of:

-   -   9.6     -   10.1     -   10.9     -   13.5     -   13.9     -   14.3     -   15.5     -   15.9     -   16.3     -   16.8     -   17.5     -   18.1     -   18.4     -   18.9     -   19.6     -   22.2     -   24.2     -   24.9     -   26.6     -   27.9     -   30.5     -   31.1     -   35.5     -   38.7

In some embodiments, Compound 1 Form C is characterized by an XRPD having one or more peaks at substantially the same angles (2 theta±0.2), corresponding to d-spacing (angstroms±0.2) of:

2 Theta d-spacing (Å) 9.6 9.3 10.1 8.8 10.9 8.1 13.5 6.6 13.9 6.4 14.3 6.2 15.5 5.7 15.9 5.6 16.3 5.4 16.8 5.3 17.5 5.1 18.1 4.9 18.4 4.8 18.9 4.7 19.6 4.5 22.2 4.0 24.2 3.7 24.9 3.6 26.6 3.3 27.9 3.2 30.5 2.9 31.1 2.9 35.5 2.5 38.7 2.3

A novel Compound 1 Form C can be identified by DSC, having two endotherms at 101.1° C. and 224.0° C. In some embodiments, Compound 1 Form C can be identified (i) by DSC having two endotherms at 101.1° C. and 224.0° C.; and (ii) by XRPD having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 15.4, 19.6, 22.3, and 26.6. In some embodiments, Compound 1 Form C is substantially free of Form B and Form X.

A novel Compound 1 Form X can be identified by XRPD, having one or more characteristic diffractions at angles (2 theta±0.2) of 7.2, 8.5, 14.9, 16.1, and 17.8. In some embodiments, Compound 1 Form X can be identified by XRPD, having one or more characteristic diffractions at angles (2 theta±0.2) of 7.2, 8.5, 14.9, 16.1, and 17.8, corresponding to d-spacing (angstroms±0.2) of 12.2, 10.4, 6.0, 5.5, and 5.0, respectively.

In some embodiments, Compound 1 Form X is characterized by an XRPD having one or more peaks at substantially the same angles (2 theta±0.2) of:

-   -   7.2     -   8.1     -   8.5     -   12.7     -   13.1     -   13.5     -   14.4     -   14.9     -   15.3     -   15.6     -   16.1     -   16.9     -   17.1     -   17.8     -   18.5     -   19.1     -   21.0     -   21.4     -   23.3     -   24.2     -   25.5     -   27.1     -   27.9     -   29.1     -   29.8     -   30.6     -   31.2     -   32.3     -   33.6     -   35.9     -   38.1.

In some embodiments, Compound 1 Form X is characterized by an XRPD having one or more peaks at substantially the same angles (2 theta±0.2), corresponding to d-spacing (angstroms±0.2) of:

2 Theta d-spacing (Å) 7.2 12.2 8.1 11.0 8.5 10.4 12.7 7.0 13.1 6.7 13.5 6.6 14.4 6.1 14.9 6.0 15.3 5.8 15.6 5.7 16.1 5.5 16.9 5.2 17.1 5.2 17.8 5.0 18.5 4.8 19.1 4.7 21.0 4.2 21.4 4.2 23.3 3.8 24.2 3.7 25.5 3.5 27.1 3.3 27.9 3.2 29.1 3.1 29.8 3.0 30.6 2.9 31.2 2.9 32.3 2.8 33.6 2.7 35.9 2.5 38.1 2.4.

A novel Compound 1 Form X can be identified by DSC, having one endotherm at 232.9° C. In some embodiments, Compound 1 Form X can be identified (i) by DSC having one endotherm at 232.9° C.; and (ii) by XRPD having one or more characteristic diffractions at angles (2 theta±0.2) of 7.2, 8.5, 14.9, 16.1, and 17.8. In some embodiments, Compound 1 Form X is substantially free of Form B and Form C.

In some embodiments, the present disclosure provides a composition comprising amorphous and crystalline solid forms of Compound 1. In some embodiments, the composition comprises crystalline Compound 1 and amorphous Compound 1, wherein the amorphous Compound 1 is present in an amount selected from the following ranges: 90-99%, 80-89%, 70-79%, 60-69%, 50-59%, 40-49%, 30-39%, 20-29%, 10-19%, 1-9% and 0-0.99%.

In some embodiments, a crystalline form of Compound 1 is anhydrous. In some embodiments, an anhydrous crystalline form of Compound 1 is selected from Mixture A, Form B, and Form X. In some embodiments, an anhydrous crystalline form of Compound 1 is Mixture A. In some embodiments, an anhydrous crystalline form of Compound 1 is Form B. In some embodiments, an anhydrous crystalline form of Compound 1 is Form X. In some embodiments, an anhydrous crystalline form of Compound 1 is a mixture of Form B and another solid form (e.g., Mixture A).

In some embodiments, a crystalline form of Compound 1 is a hydrate. In some embodiments, a hydrate crystalline form of Compound 1 is Form C.

A pharmaceutical composition can comprise and/or be obtained from the solid form of Compound 1, designated as Form B, that produces an XRPD pattern having one or more diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3. In some embodiments, the pharmaceutical composition can comprise and/or be obtained from Compound 1 Form B, which can be identified by an XRPD pattern having one or more diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3, corresponding to d-spacing (angstroms±0.2) of 9.2, 8.7, 5.7, 4.5, and 4.0. In some embodiments, the pharmaceutical composition can comprise and/or be obtained from Compound 1 Form B, which can be identified by XRPD, (i) having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3; and (ii) not having a characteristic diffraction at an angle (2 theta±0.2) of 24.2. In some embodiments, the pharmaceutical composition can comprise and/or be obtained from Compound 1 Form B, which can be identified by XRPD, (i) having one or more characteristic diffractions at angles (2 theta±0.2) of 15.4, 19.6, and 22.3; and (ii) not having a characteristic diffraction at an angle (2 theta±0.2) of 24.2. In some embodiments, the pharmaceutical composition can comprise and/or be obtained from Compound 1 Form B, which can be identified by XRPD (i) having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3, and (ii) not having one or more characteristic diffractions at angles (2 theta±0.2) of 7.2, 8.5, 14.9, 16.1, and 17.8. In some embodiments, the pharmaceutical composition can comprise and/or be obtained from Compound 1 Form B, which can be identified by XRPD, (i) having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3; (ii) not having a characteristic diffraction at an angle (2 theta±0.2) of 24.2; and (iii) not having one or more characteristic diffractions at angles (2 theta±0.2) of 7.2, 8.5, 14.9, 16.1, and 17.8. In some embodiments, the pharmaceutical composition can comprise any one of the solid forms of Compound 1 described herein. In some embodiments, the pharmaceutical composition is substantially free of Compound 1 Form X. In some embodiments, the pharmaceutical composition can comprise and/or be obtained from a solid form consisting of Compound 1 Form B.

A pharmaceutical composition can comprise and/or be obtained from the solid form of Compound 1, designated as Form B, that can be identified by DSC, having one endotherm at 225.7° C. In some embodiments, the pharmaceutical composition can comprise and/or be obtained from Compound 1 Form B, which can be identified (i) by DSC having one endotherm at 225.7° C.; and (ii) by XRPD having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3. In some embodiments, the pharmaceutical composition can comprise and/or be obtained from Compound 1 Form B, which can be identified (i) by DSC having one endotherm at 225.7° C.; (ii) by XRPD having one or more characteristic diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3; and (iii) by XRPD not having one or more characteristic diffractions at angles (2 theta±0.2) of 7.2, 8.5, 14.9, 16.1, 17.8, and 24.2.

Pharmaceutical compositions reported herein can be combined with a pharmaceutically acceptable carrier or excipient. In some embodiments, pharmaceutical compositions reported herein can be provided in a unit dosage form container (e.g., in a vial or bag or the like). In some embodiments, pharmaceutical compositions reported herein can be provided in an oral dosage form. In some embodiments, an oral dosage form is a capsule. In some embodiments, an oral dosage form is a tablet.

In some embodiments, the present disclosure provides methods of inhibiting FASN, comprising administering a solid form of Compound 1 to a subject. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition responsive to inhibition of FASN, comprising administering a solid form of Compound 1 to a subject in need thereof. In some embodiments, the disease, disorder, or condition is non-alcoholic steatohepatitis (NASH).

In some embodiments, the present disclosure relates to:

1. Crystalline (4-(2-fluoro-4-(1-methyl-H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone. 2. A solid form of Compound 1:

3. The solid form of embodiment 2, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3. 4. The solid form of embodiment 3, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3, and not having one or more diffractions at angles (2 theta±0.2) of 7.2, 8.5, 14.9, 16.1, and 17.8. 5. The solid form of embodiment 3 or 4, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3 and not having a diffraction at angle (2 theta±0.2) of 24.2. 6. The solid form of any one of the preceding embodiments, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3, corresponding to d-spacing (A±0.2) of 9.2, 8.7, 5.7, 4.5, and 4.0, respectively. 7. The solid form of any one of the preceding embodiments, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of:

-   -   9.6     -   10.1     -   10.7     -   12.6     -   13.9     -   14.3     -   15.4     -   16.4     -   16.6     -   17.4     -   18.2     -   18.5     -   19.6     -   20.2     -   22.1     -   22.3     -   23.4     -   23.8     -   25.0     -   25.3     -   26.5     -   26.9     -   28.0     -   29.0     -   29.5     -   30.5     -   31.1     -   31.8     -   32.9     -   34.1     -   37.3     -   37.9.         8. The solid form of any one of the preceding embodiments,         wherein the solid form is characterized by an XRPD pattern         having diffractions at angles (2 theta±0.2) corresponding to         d-spacing (Å±0.2) of:

2 Theta d-spacing (Å) 9.6 9.2 10.1 8.7 10.7 8.3 12.6 7.0 13.9 6.4 14.3 6.2 15.4 5.7 16.4 5.4 16.6 5.3 17.4 5.1 18.2 4.9 18.5 4.8 19.6 4.5 20.2 4.4 22.1 4.0 22.3 4.0 23.4 3.8 23.8 3.7 25.0 3.6 25.3 3.5 26.5 3.4 26.9 3.3 28.0 3.2 29.0 3.1 29.5 3.0 30.5 2.9 31.1 2.9 31.8 2.8 32.9 2.7 34.1 2.6 37.3 2.4 37.9 2.4. 9. The solid form of any one of the preceding embodiments, wherein the solid form is characterized by an XRPD pattern expressed in terms of angles (2 theta±0.2) and obtained with a diffractometer according to one or more parameters from Table 1, and wherein the X-ray powder diffraction pattern comprises diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3. 10. The solid form of any one of the preceding embodiments, wherein the solid form is characterized by a DSC endotherm having an endotherm at about 226° C. 11. The solid form of any one of the preceding embodiments, wherein the solid form is characterized by a DSC endotherm expressed in terms of degrees and obtained with a calorimeter according to one or more parameters from Table 3, wherein the DSC endotherm is at about 226° C. 12. The solid form of any one of the preceding embodiments, wherein the solid form is characterized by a TGA with a weight loss of about 0.5% between 21° C. and 100° C. 13. The solid form of any one of the preceding embodiments, wherein the solid form is characterized by a DVS of about 0.5% water by weight below 95% relative humidity. 14. The solid form of any one of the preceding embodiments, wherein the solid form is Solid Form B. 15. The solid form of embodiment 2, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 15.4, 19.6, 22.3, and 26.6. 16. The solid form of embodiment 15, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 15.4, 19.6, 22.3, and 26.6, corresponding to d-spacing (Å±0.2) of 9.3, 5.7, 4.5, 4.0, and 3.3, respectively. 17. The solid form of embodiment 15 or 16, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of:

-   -   9.6     -   10.1     -   10.9     -   13.5     -   13.9     -   14.3     -   15.5     -   15.9     -   16.3     -   16.8     -   17.5     -   18.1     -   18.4     -   18.9     -   19.6     -   22.2     -   24.2     -   24.9     -   26.6     -   27.9     -   30.5     -   31.1     -   35.5     -   38.7         18. The solid form of any one of embodiments 15-17, wherein the         solid form is characterized by an XRPD pattern having         diffractions at angles (2 theta±0.2) corresponding to d-spacing         (Å±0.2) of:

2 Theta d-spacing (Å) 9.6 9.3 10.1 8.8 10.9 8.1 13.5 6.6 13.9 6.4 14.3 6.2 15.5 5.7 15.9 5.6 16.3 5.4 16.8 5.3 17.5 5.1 18.1 4.9 18.4 4.8 18.9 4.7 19.6 4.5 22.2 4.0 24.2 3.7 24.9 3.6 26.6 3.3 27.9 3.2 30.5 2.9 31.1 2.9 35.5 2.5 38.7 2.3 19. The solid form of any one of embodiments 15-18, wherein the solid form is characterized by an X-ray powder diffraction pattern expressed in terms of angles (2 theta±0.2) and obtained with a diffractometer according to one or more parameters from Table 1, and wherein the X-ray powder diffraction pattern comprises diffractions at angles (2 theta±0.2) of 9.6, 15.4, 19.6, 22.3, and 26.6. 20. The solid form of any one of embodiments 15-19, wherein the solid form is characterized by a DSC endotherm having two endotherms at about 101.1° C. and about 224.0° C. 21. The solid form of any one of embodiments 15-20, wherein the solid form is characterized by a DSC endotherm expressed in terms of degrees and obtained with a calorimeter according to one or more parameters from Table 3, wherein the DSC endotherm is at about 101.1° C. and about 224.0° C. 22. The solid form of any one embodiments 15-21, wherein the solid form is characterized by a TGA with a weight loss of about 5.77% between 21° C. and 100° C. 23. The solid form of any one of embodiments 15-22, wherein the solid form is Solid Form C. 24. The solid form of embodiment 2, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 7.2, 8.5, 14.9, 16.1, and 17.8. 25. The solid form of embodiment 24, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 7.2, 8.5, 14.9, 16.1, and 17.8, corresponding to d-spacing (Å±0.2) of 12.2, 10.4, 6.0, 5.5, and 5.0, respectively. 26. The solid form of embodiment 24 or 25, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of:

-   -   7.2     -   8.1     -   8.5     -   12.7     -   13.1     -   13.5     -   14.4     -   14.9     -   15.3     -   15.6     -   16.1     -   16.9     -   17.1     -   17.8     -   18.5     -   19.1     -   21.0     -   21.4     -   23.3     -   24.2     -   25.5     -   27.1     -   27.9     -   29.1     -   29.8     -   30.6     -   31.2     -   32.3     -   33.6     -   35.9     -   38.1.         27. The solid form of any one of embodiments 24-26, wherein the         solid form is characterized by an XRPD pattern having         diffractions at angles (2 theta±0.2) corresponding to d-spacing         (Å±0.2) of:

2 Theta d-spacing (Å) 7.2 12.2 8.1 11.0 8.5 10.4 12.7 7.0 13.1 6.7 13.5 6.6 14.4 6.1 14.9 6.0 15.3 5.8 15.6 5.7 16.1 5.5 16.9 5.2 17.1 5.2 17.8 5.0 18.5 4.8 19.1 4.7 21.0 4.2 21.4 4.2 23.3 3.8 24.2 3.7 25.5 3.5 27.1 3.3 27.9 3.2 29.1 3.1 29.8 3.0 30.6 2.9 31.2 2.9 32.3 2.8 33.6 2.7 35.9 2.5 38.1 2.4. 28. The solid form of any one of embodiments 24-27, wherein the solid form is characterized by an XRPD pattern expressed in terms of angles (2 theta±0.2) and obtained with a diffractometer according to one or more parameters from Table 1, and wherein the X-ray powder diffraction pattern comprises diffractions at angles (2 theta±0.2) of 7.2, 8.5, 14.9, 16.1, and 17.8. 29. The solid form of any one of embodiments 24-28, wherein the solid form is characterized by a DSC endotherm having an endotherm at about 232.9° C. 30. The solid form of any one embodiments 24-29, wherein the solid form is characterized by a DSC endotherm expressed in terms of degrees and obtained with a calorimeter according to one or more parameters from Table 3, wherein the DSC endotherm is at about 232.9° C. 31. The solid form of any one embodiments 24-30, wherein the solid form is characterized by a TGA with a weight loss of about 0.47% between 21° C. and 150° C. 32. The solid form of any one of embodiments 24-31, wherein the solid form is Solid Form X. 33. A composition comprising a mixture of solid forms of Compound 1:

34. The composition of embodiment 33, wherein the composition is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3. 35. The composition of embodiment 33 or 34, wherein the solid form mixture is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3, corresponding to d-spacing (Å±0.2) of 9.3, 8.7, 5.7, 4.5, and 4.0, respectively. 36. The composition of any one of embodiments 33-35, wherein the solid form mixture is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) corresponding to d-spacing (Å±0.2) of:

-   -   7.9     -   9.6     -   10.1     -   10.7     -   12.6     -   13.4     -   13.9     -   14.3     -   15.4     -   16.3     -   16.8     -   17.4     -   18.5     -   19.6     -   20.2     -   21.0     -   21.4     -   22.1     -   22.2     -   23.4     -   23.8     -   25.0     -   25.3     -   26.5     -   26.8     -   27.2     -   28.0     -   29.0     -   29.4     -   30.5     -   31.1     -   31.8     -   32.9     -   33.6     -   34.1     -   37.3     -   37.9.         37. The composition of any one of embodiments 33-36, wherein the         solid form is characterized by an XRPD pattern having         diffractions at angles (2 theta±0.2) corresponding to d-spacing         (A±0.2) of:

2 Theta d-spacing (Å) 7.9 11.1 9.6 9.3 10.1 8.7 10.7 8.3 12.6 7.0 13.4 6.6 13.9 6.4 14.3 6.2 15.4 5.7 16.3 5.4 16.8 5.3 17.4 5.1 18.5 4.8 19.6 4.5 20.2 4.4 21.0 4.2 21.4 4.2 22.1 4.0 22.2 4.0 23.4 3.8 23.8 3.7 25.0 3.6 25.3 3.5 26.5 3.4 26.8 3.3 27.2 3.3 28.0 3.2 29.0 3.1 29.4 3.0 30.5 2.9 31.1 2.9 31.8 2.8 32.9 2.7 33.6 2.7 34.1 2.6 37.3 2.4 37.9 2.4. 38. The solid form of any one of embodiments 33-37, wherein the solid form is characterized by an XRPD pattern expressed in terms of angles (2 theta±0.2) and obtained with a diffractometer according to one or more parameters from Table 1, and wherein the X-ray powder diffraction pattern comprises diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3. 39. The composition of any one of embodiments 33-38, wherein the solid form mixture is characterized by a DSC endotherm having two endotherms at about 226.2° C. and about 229.1° C. 40. The solid form of any one embodiments 33-39, wherein the solid form is characterized by a DSC endotherm expressed in terms of degrees and obtained with a calorimeter according to one or more parameters from Table 3, wherein the DSC endotherm is at about 226.2° C. and about 229.1° C. 41. The composition of any one embodiments 33-40, wherein the solid form mixture is characterized by a TGA with a weight loss of about 1.73% between 21° C. and 150° C. 42. The composition of any one of embodiments 33-41, wherein the solid form mixture is Solid Form Mixture A. 43. A pharmaceutical composition comprising a solid form of Compound 1:

and a pharmaceutically acceptable carrier. 44. The pharmaceutical composition of embodiment 43, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3. 45. The pharmaceutical composition of embodiment 43 or 44, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3, and not having one or more diffractions at angles (2 theta±0.2) of 7.2, 8.5, 14.9, 16.1, and 17.8. 46. The pharmaceutical composition of any one of embodiments 43-45, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3 and not having a diffraction at angle (2 theta±0.2) of 24.2. 47. The pharmaceutical composition of any one of embodiments 43-46, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3, corresponding to d-spacing (Å±0.2) of 9.2, 8.7, 5.7, 4.5, and 4.0, respectively. 48. The pharmaceutical composition of any one of embodiments 43-47, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of:

-   -   9.6     -   10.1     -   10.7     -   12.6     -   13.9     -   14.3     -   15.4     -   16.4     -   16.6     -   17.4     -   18.2     -   18.5     -   19.6     -   20.2     -   22.1     -   22.3     -   23.4     -   23.8     -   25.0     -   25.3     -   26.5     -   26.9     -   28.0     -   29.0     -   29.5     -   30.5     -   31.1     -   31.8     -   32.9     -   34.1     -   37.3     -   37.9.         49. The pharmaceutical composition of any one of embodiments         43-48, wherein the solid form is characterized by an XRPD         pattern having diffractions at angles (2 theta±0.2)         corresponding to d-spacing (Å±0.2) of:

2 Theta d-spacing (Å) 9.6 9.2 10.1 8.7 10.7 8.3 12.6 7.0 13.9 6.4 14.3 6.2 15.4 5.7 16.4 5.4 16.6 5.3 17.4 5.1 18.2 4.9 18.5 4.8 19.6 4.5 20.2 4.4 22.1 4.0 22.3 4.0 23.4 3.8 23.8 3.7 25.0 3.6 25.3 3.5 26.5 3.4 26.9 3.3 28.0 3.2 29.0 3.1 29.5 3.0 30.5 2.9 31.1 2.9 31.8 2.8 32.9 2.7 34.1 2.6 37.3 2.4 37.9 2.4. 50. The solid form of any one of embodiments 43-49, wherein the solid form is characterized by an XRPD pattern expressed in terms of angles (2 theta±0.2) and obtained with a diffractometer according to one or more parameters from Table 1, and wherein the X-ray powder diffraction pattern comprises diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3. 51. The pharmaceutical composition of any one of embodiments 43-50, wherein the solid form is characterized by a DSC endotherm having an endotherm at about 226° C. 52. The solid form of any one of embodiments 43-51, wherein the solid form is characterized by a DSC endotherm expressed in terms of degrees and obtained with a calorimeter according to one or more parameters from Table 3, wherein the DSC endotherm is at about 226° C. 53. The pharmaceutical composition of any one of embodiments 43-52, wherein the solid form is characterized by a TGA with a weight loss of about 0.5% between 21° C. and 100° C. 54. The pharmaceutical composition of any one of embodiments 43-53, wherein the solid form is characterized by a DVS of about 0.5% water by weight below 95% relative humidity. 55. The pharmaceutical composition of any one of embodiments 43-54, wherein the solid form is Solid Form B. 56. A process for preparing Solid Form B of (4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (Compound 1) comprising suspending at least one of Mixture A, Form C, and Form X in a solvent to provide a slurry, and maintaining the slurry for a period of time under conditions effective to generate Solid Form B of Compound 1. 57. The process of embodiment 56, wherein the solvent is selected from the group consisting of ethyl acetate (EtOAc), acetonitrile (ACN), heptane, isopropyl alcohol (IPA), and ethanol (EtOH). 58. The process of embodiment 56 or 57, wherein the slurry is heated to a temperature from about 50° C. to about 100° C. after suspension in the solvent. 59. The process of any one of embodiments 56-58, further comprising isolating Solid Form B of Compound 1 from the slurry. 60. A solid form obtained by a process described herein. 61. The solid form of embodiment 60, wherein the solid form is Form B. 62. The solid form of embodiment 60, wherein the solid form is Form C. 63. The solid form of embodiment 60, wherein the solid form is Form X. 64. A composition obtained by a process described herein. 65. The composition of embodiment 64, wherein the composition is Solid Form Mixture A.

In some embodiments, the present disclosure relates to:

1. Crystalline (4-(2-fluoro-4-(1-methyl-H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone. 2. A solid form of Compound 1:

3. The solid form of embodiment 2, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3. 4. The solid form of embodiment 3, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3 and not having a diffraction at angle (2 theta±0.2) of 24.2. 5. The solid form of embodiment 2, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 15.4, 19.6, and 22.3 and not having a diffraction at angle (2 theta±0.2) of 24.2. 6. The solid form of any one of the preceding embodiments, wherein the solid form is characterized by a DSC endotherm having an endotherm at about 226° C. 7. The solid form of any one of the preceding embodiments, wherein the solid form is characterized by a TGA with a weight loss of about 0.5% between 21° C. and 100° C. 8. The solid form of any one of the preceding embodiments, wherein the solid form is characterized by a DVS of about 0.5% water by weight below 95% relative humidity. 9. The solid form of any one of the preceding embodiments, wherein the solid form is Solid Form B. 10. The solid form of embodiment 2, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 15.4, 19.6, 22.3, and 26.6. 11. The solid form of embodiment 2, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 15.4, 19.6, 22.3, 24.2, and 26.6. 12. The solid form of embodiment 2, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 7.2, 8.5, 14.9, 16.1, and 17.8. 13. A composition comprising a mixture of solid forms of Compound 1:

14. The composition of embodiment 13, wherein the composition is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3. 15. The composition of embodiment 13, wherein the composition is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, 21.0, and 22.3. 16. A pharmaceutical composition comprising a solid form of Compound 1:

and a pharmaceutically acceptable carrier. 17. The pharmaceutical composition of embodiment 16, wherein the solid form of Compound 1 is the solid form of any one of embodiments 1-12. 18. The pharmaceutical composition of embodiment 16, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3. 19. The pharmaceutical composition of any one of embodiments 16-18, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3 and not having a diffraction at angle (2 theta±0.2) of 24.2. 20. The pharmaceutical composition of embodiment 16, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 15.4, 19.6, and 22.3 and not having a diffraction at angle (2 theta±0.2) of 24.2. 21. The pharmaceutical composition of any one of embodiments 16-20, wherein the solid form is Solid Form B. 22. The pharmaceutical composition of any one of embodiments 16-21, wherein the pharmaceutical composition is substantially free of Solid Form X. 23. The pharmaceutical composition of embodiment 16, wherein the solid form consists of Solid Form B. 24. A process for preparing Solid Form B of (4-(2-fluoro-4-(1-methyl-H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (Compound 1) comprising suspending at least one of Mixture A, Form C, and Form X in a solvent to provide a slurry, and maintaining the slurry for a period of time under conditions effective to generate Solid Form B of Compound 1. 25. The process of embodiment 24, wherein the solvent is selected from the group consisting of ethyl acetate (EtOAc), acetonitrile (ACN), heptane, isopropyl alcohol (IPA), and ethanol (EtOH). 26. The process of embodiment 24 or 25, wherein the slurry is heated to a temperature from about 50° C. to about 100° C. after suspension in the solvent. 27. The process of any one of embodiments 24-26, further comprising isolating Solid Form B of Compound 1 from the slurry. 28. A solid form of Compound 1:

wherein the solid form is the form that would be obtained by a process comprising:

suspending at least one of Mixture A, Form C, and Form X of Compound 1 in a solvent selected from a group consisting of ethyl acetate (EtOAc), acetonitrile (ACN), heptane, isopropyl alcohol (IPA), and ethanol (EtOH) to provide a slurry; and

maintaining the slurry for a period of at least 5 hours to afford the solid form of Compound 1.

29. The solid form of embodiment 28, wherein the slurry is heated to a temperature from about 50° C. to about 100° C. after suspension in the solvent. 30. The solid form of embodiment 28 or 29, further comprising isolating the solid form of Compound 1 from the slurry.

Examples Instrumentation and Methods

Unless otherwise indicated, the following instrumentation and methods were used in the working examples described herein.

X-Ray Powder Diffraction (XRPD)

High resolution XRPD experiments were performed with Panalytical X'Pert³ Powder XRPD on a Si zero-background holder. The 20 position was calibrated against Panalytical 640 Si powder standard. Details of the XRPD method are listed in Table 1 below:

TABLE 1 Parameters for Reflection Mode X-Ray wavelength Cu, kα, Kα1 (Å): 1.540598, Kα2 (Å): 1.544426 Kα2/Kα1 intensity ratio: 0.50 X-Ray tube setting 45 kV, 40 mA Divergence slit Automatic Scan mode Continuous Scan range (°2TH) 3°-40° Step size (°2TH) 0.0262606 Scan speed (°/s) 0.066482

Peaks are reported as diffraction angles at 2 theta, with d-spacing measured in angstroms.

Thermal Analysis

TGA experiments were performed on TA Q500 TGA from TA Instruments. Samples were heated at 10° C./min from about 20° C. to about 350° C. using dry nitrogen to purge the system. The details of the method are provided in Table 2, below:

TABLE 2 Parameters TGA Temperature RT-350° C. Ramp rate 10° C./min Purge gas N₂

DSC experiments were performed on TA Q2000 DSC from TA Instruments. Samples were heated at 10° C./min from about 20° C. to about 350° C. using dry nitrogen to purge the system. The details of the method are providing in Table 3, below:

TABLE 3 Parameters DSC Temperature RT-350° C. Ramp rate 10° C./min Purge gas N₂

Dynamic Vapor Sorption

DVS was obtained using a Surface Measurement Systems (SMS) DVS Intrinsic. The details of the method are providing in Table 4, below:

TABLE 4 Parameters Values Temperature 25° C. Sample size 10-20 mg Gas and flow rate N₂, 200 mL/min dm/dt 0.002%/min Min. dm/dt stability duration 10 min Max. equilibrium time 360 min Relative humidity (RH) range 20% RH-95% RH-0% RH-95% RH Relative humidity (RH) step size 10%

High Pressure Liquid Chromatography

High Pressure Liquid Chromatography (HPLC) data was obtained according to Table 5, below:

TABLE 5 HPLC Method Parameters Instrument Agilent 1100 HPLC with DAD detector Column Waters Xbridge C18, 100 Å, 3.5 μm, 4.6 × 150 mm Mobile Phase A: 0.1% TFA in H₂O B: 0.1% TFA in acetonitrile Time (min) B % Gradient 0.00 5 10.00 25 15.00 45 20.00 90 21.00 5 Flow Rate 1 mL/min Wave length UV at 240 nm Injection Volume 10 μL Run time 25 min Column Temperature 35° C. Sample temperature Ambient Diluent water/acetonitrile (3/1 v/v) Target analytical ~0.1 mg/ml concentration

Example 1—Synthesis of (4-(2-fluoro-4-(1-methyl-H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

The synthesis of (4-(2-fluoro-4-(1-methyl-H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (“Compound 1”) was previously reported in PCT Application Publication No. WO 2014/164749. Compound 1 may be prepared as shown below:

Step 1. tert-butyl 4-(4-bromo-2-fluorobenzoyl)piperazine-1-carboxylate

A 5 L multi-neck round bottom flask fitted with nitrogen inlet and overhead stirring was charged with 4-bromo-2-fluorobenzoyl chloride (100 g, 421 mmol), tert-butyl piperazine-1-carboxylate (78 g, 421 mmol), dimethylformamide (DMF) (750 mL), and diisopropylethylamine ((i-Pr)₂NEt; DIEA) (221 mL, 1263 mmol). The mixture was stirred at room temperature (rt) and monitored by liquid chromatography/mass spectrometry (LC/MS) for completion. Upon completion (ca. 2 hours) 0.2 M HC (300 mL) was slowly added while maintaining internal temperature below 35° C. The heterogeneous mixture was stirred at rt for 3 hours, and then the solids were isolated by filtration. The reaction vessel and solids were washed with water (300 mL) and the solids were dried under house vacuum (17 torr) to afford tert-butyl 4-(4-bromo-2-fluorobenzoyl)piperazine-1-carboxylate (151 g, 93% yield) as an off white solid.

Step 2. (4-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)-3-fluorophenyl)boronic Acid

A 5 L multi-neck round bottom flask fitted with nitrogen inlet, overhead stirring, thermocouple and condenser was charged with tert-butyl 4-(4-bromo-2-fluorobenzoyl)piperazine-1-carboxylate (125 g, 323 mmol), potassium acetate (79 g, 807 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (102 g, 403 mmol), 2-methyl tetrahydrofuran (1250 mL). The mixture was sparged with nitrogen and then PdCl₂(dppf) was added (2.362 g, 3.23 mmol). The mixture was heated to 75° C. and monitored for completion by LC/MS. Upon completion (about 24 hours) the mixture was cooled to rt and diluted with water (1250 mL). The bi-phasic mixture was filtered through celite, and the reaction vessel and celite were washed with fresh 2-methyltetrahydrofuran (250 mL). The phases were separated and the organic phase was washed with water (1250 mL). The organic phase was diluted with 1M NaOH (1250 mL) and the phases separated. The aqueous (product containing) phase was diluted with fresh 2-methyltetrahydrofuran (1400 mL), and the pH was adjusted to 1.0 with 6 M HCl. The phases were separated, and the organic (product containing) phase was filtered through celite and added to a 5 L multi-neck round bottom flask fitted with nitrogen inlet and overhead stirring, containing water (1400 mL) and sodium periodate (110 g, 516 mmol). The mixture was stirred for 1 hour, followed by the addition of 1 M HCl (980 ml). The mixture was stirred at rt and monitored for completion by LC/MS. Upon completion (about 18 hours) the phases were separated, and the organic phase was washed with 20 wt % aqueous Na₂S₂O₃ (500 mL), water (500 mL), and brine (500 mL). The organic phase was dried with magnesium sulfate, filtered, and the solids washed with fresh 2-methyltetrahydrofuran (200 mL). The filtrate was concentrated to dryness under reduced pressure to afford (4-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)-3-fluorophenyl)boronic acid (100.22 g, 88% yield) as a tan solid.

Step 3. tert-butyl 4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazine-1-carboxylate

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (4-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)-3-fluorophenyl)boronic acid (620 mg, 1.42 mmol, 1.00 equiv), toluene (10 mL), 5-bromo-1-methyl-1H-1,3-benzodiazole (300 mg, 1.42 mmol, 1.00 equiv), Pd(PPh₃)4 (198 mg, 0.17 mmol, 0.12 equiv), sodium carbonate (2 M, 5 mL), and ethanol (1.4 mL). The resulting mixture was stirred overnight at 95° C. After cooling to room temperature, the mixture was diluted with 20 mL H₂O, extracted with 3×30 mL of ethyl acetate. All the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was loaded onto a silica gel column with dichloromethane/methanol (95:5). The collected fractions were combined and concentrated under vacuum. This resulted in 600 mg (96%) of tert-butyl 4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazine-1-carboxylate as a yellow solid. LC-MS (ES, m/z): 439 [M+H]+.

Step 4. (2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)(piperazin-1-yl)methanone (Hydrochloride Salt)

Into a 100-mL round-bottom flask, was placed a solution of tert-butyl 4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazine-1-carboxylate (600 mg, 1.37 mmol, 1.00 equiv) in ethyl acetate (EA)/THF (1:1, 20 mL). Hydrogen chloride gas was then bubbled into the reaction mixture. The solution was stirred for 30 min at room temperature. The solids were collected by filtration and dried under reduced pressure. This resulted in 460 mg (100%) of (2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)(piperazin-1-yl)methanone (hydrochloride salt) as an off-white solid. LC-MS (ES, m/z): 339 [M+H]⁺.

Step 5. (4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

Into a 100-mL round-bottom flask, was placed a solution of (2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)(piperazin-1-yl)methanone (hydrochloride salt) (398 mg, 1.18 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL), 1-hydroxycyclopropane-1-carboxylic acid (120 mg, 1.18 mmol, 1.00 equiv), HBTU (669 mg, 1.76 mmol, 1.50 equiv), and DIEA (608 mg, 4.70 mmol, 4.00 equiv). The resulting mixture was stirred overnight at room temperature. The solution was diluted with 30 mL of EA, washed with 3×30 mL H₂O. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with EA/petroleum ether (0:100-100:0). The collected fractions were combined and concentrated under vacuum to dryness. This resulted in 152.8 mg (31%) of (4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone as a white solid. LC-MS: (ES, m/z): 423[M+H]⁺. ¹H-NMR: (CD₃OD, 300 MHz): δ 8.20 (s, 1H), 7.96 (s, 1H), 7.68-7.63 (m, 3H), 7.59-7.50 (m, 2H), 3.95-3.72 (m, 9H), 3.50 (s, 2H), 1.10-1.06 (m, 2H), 0.93-0.89 (m, 2H).

Example 2—Characterization of Solid Forms and Solid Form Mixtures of Compound 1 Mixture A

Compound 1 Mixture A was prepared by replacing step 5 of Example 1 with step 6:

Step 6: (4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

To a solution of 1-hydroxycyclopropane-1-carboxylic acid (30 g, 294 mmol) in DMF (900 mL) was added HBTU (36 g, 95.6 mmol), 5-[3-fluoro-4-[(piperazin-1-yl)carbonyl]phenyl]-1-methyl-1H-1,3-benzodiazole hydrochloride (8.6 g, 22.9 mmol), and DIEA (52.8 mL, 319 mmol). The resulting solution was stirred for 18 hours at 20° C. The reaction mixture was poured into water (4 L) and then extracted with DCM (4×1.5 L). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting crude product was purified by reversed phase chromatography (5% to 35% MeCN/water (containing 0.1% NH₄HCO₃) over 30 min). The fractions were collected and lyophilized. The product was further purified by recrystallization with MeOH/water (1:2) and dried under vacuum to afford 1-[(4-[[2-fluoro-4-(1-methyl-1H-1,3-benzodiazol-5-yl)phenyl]carbonyl]piperazin-1-yl)carbonyl]cyclopropan-1-ol as a white solid (11.46 g, 33.9%). The XRPD pattern of the crystalline Compound 1 Mixture A is depicted in FIG. 1, and the corresponding data is summarized below:

2 Theta d-spacing (Å) 7.9 11.1 9.6 9.3 10.1 8.7 10.7 8.3 12.6 7.0 13.4 6.6 13.9 6.4 14.3 6.2 15.4 5.7 16.3 5.4 16.8 5.3 17.4 5.1 18.5 4.8 19.6 4.5 20.2 4.4 21.0 4.2 21.4 4.2 22.1 4.0 22.2 4.0 23.4 3.8 23.8 3.7 25.0 3.6 25.3 3.5 26.5 3.4 26.8 3.3 27.2 3.3 28.0 3.2 29.0 3.1 29.4 3.0 30.5 2.9 31.1 2.9 31.8 2.8 32.9 2.7 33.6 2.7 34.1 2.6 37.3 2.4 37.9 2.4

As shown by TGA and DSC curves in FIG. 2, Mixture A showed a weight loss of 1.73% up to 150° C. and two endotherms at 226.2° C. and 229.1° C. (peak temperature) before decomposition.

Without wishing to be bound by any particular theory, Applicant has observed that Mixture A is an apparent mixture of two anhydrous forms: Form B and another solid form, as is apparent from the extra reflections in XRPD (FIG. 1) and additional endotherms in DSC (FIG. 2), compared with Form B alone.

Form B

Compound 1 Form B was prepared by one of the following procedures.

Procedure 1: Mixture A (0.10 g) was recrystallized from ACN-water (ca. 9:1, 10 volumes) to give Form B in 72% recovery.

Procedure 2: Form C (0.25 g) was slurried in heptane (40 volumes) at 100° C. for 7 hours, then cooled to room temperature and filtered to give Form B in 80% recovery, 98.95% purity.

Procedure 3: Form C (0.25 g) was slurried in IPA (40 volumes) at 80° C. for 7 hours, then cooled to room temperature and filtered to give Form B in 60% recovery, 99.02% purity.

Procedure 4: Form C (21 g) was slurried in heptane (10 volumes) at 105° C. for 5 hours, then cooled to room temperature, and filtered to give Form B in 91% recovery, 98.79% purity.

Procedure 5: Form C (30 g) was combined in IPA (15 volumes) and heated to reflux. IPA (7.5 volumes) was then distilled off. The resulting suspension was cooled to room temperature, filtered and dried at 50° C. and 80° C. to give 91% recovery, 99.27% purity.

Procedure 6: Form C (1.0 g) was dissolved in N-methyl-2-pyrrolidone (NMP) (9 volumes) at 50° C. The solution was cooled to room temperature and filtered. IPA (18 volumes) was added to the filtrate, then Form B seed crystals were added. The slurry was stirred at room temperature, filtered and dried to give 73% recovery, 99.48% purity.

Procedure 7: Form C (25 g) was slurried in ethanol (15 volumes) at 50° C. for 8 hours. The slurry was cooled to rt and filtered to give 99.51% purity.

Procedure 8: The final step of Example 1 was replaced with step 6:

Step 6: (4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

A 250-mL round-bottomed flask was charged with (2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)(piperazin-1-yl)methanone (hydrochloride salt) (10.36 g, 1.00 equiv), HOBt (861 mg, 1.30 equiv), and EtOH (40 mL). With moderate agitation, the suspension was charged with 3 M NaOH (aq) (19.0 mL, 2.35 equiv), and the reaction mixture was agitated at room temperature for 10 minutes. The reaction mixture was filter using a Buchner funnel to give a first solution. A separate 100-mL round-bottomed flask was charged with EDC HCl (5.59 g, 1.2 equiv) and 25 mL EtOH. The resulting mixture was agitated at room temperature for 10 minutes, and then filtered using a Buchner funnel to give a second solution. To the first solution was added the second solution over the course of an hour. The reaction mixture was agitated at room temperature for about 7 hours. The reaction mixture was then added to water (250 mL) in portions over the course of an hour, and the resulting mixture was agitated for about 3 hours. The reaction mixture was filtered using a Buchner funnel and washed with water (100 mL) to give (4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone in about 90% yield.

The XRPD pattern of the crystalline Compound 1 Form B is depicted in FIG. 3, and the corresponding data is summarized below:

2 Theta d-spacing (Å) 9.6 9.2 10.1 8.7 10.7 8.3 12.6 7.0 13.9 6.4 14.3 6.2 15.4 5.7 16.4 5.4 16.6 5.3 17.4 5.1 18.2 4.9 18.5 4.8 19.6 4.5 20.2 4.4 22.1 4.0 22.3 4.0 23.4 3.8 23.8 3.7 25.0 3.6 25.3 3.5 26.5 3.4 26.9 3.3 28.0 3.2 29.0 3.1 29.5 3.0 30.5 2.9 31.1 2.9 31.8 2.8 32.9 2.7 34.1 2.6 37.3 2.4 37.9 2.4

As shown by TGA and DSC curves in FIG. 4, Form B showed a weight loss of 0.45% up to 100° C. and one endothermic peak at 223.9° C. (onset temperature); 225.7° C. (peak temperature) before decomposition.

DVS analysis was also conducted for Form B. As shown in FIG. 5, a mass change of 0.46 wt % was observed for Form B from 0% RH to 95% RH at 25° C. The sample was non-hygroscopic. As shown by XRPD in FIG. 6, no form change was observed for Form B before and after DVS.

A study was conducted on a sample of Compound 1 (Form B) where samples were exposed (open) to a range of elevated temperatures (50-80° C.) and controlled relative humidity (RH) (0-80% RH). Compound 1 exhibits good chemical stability, and the estimated shelf life is greater than 5 years at 25° C./60% RH.

Form C

Compound 1 Form C was prepared by replacing step 5 of Example 1 with either step 7a or step 7b:

Step 7a: (4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

To a 2-L, three-necked, round-bottomed flask fitted with a nitrogen inlet, and overhead stirring was added (2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)(piperazin-1-yl)methanone dihydrochloride (139.21 g, 338 mmol), 1-hydroxycyclopropanecarboxylic acid (44.9 g, 440 mmol), 1-hydroxybenzotriazole hydrate (10.37 g, 67.7 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (84 g, 440 mmol), dimethyl sulfoxide (DMSO) (700 mL), and 4-methylmorpholine (167 mL, 1523 mmol). The mixture stirred at rt and monitored for completion by LC/MS. Upon reaction completion (ca. 18 hours) the mixture was added to a 5-L, three-necked, round-bottomed flask fitted with a nitrogen inlet and overhead stirring containing water (2800 mL). The mixture was granulated for 24 hours and then filtered. The isolated solids were then stirred in water (1200 mL) at rt for 4 hours, filtered, and washed with water (300 mL). The solids were dried on filter under a nitrogen atmosphere followed by house vacuum (ca. 17 torr) to afford (4-(2-fluoro-4-(1-methyl-H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (118.7 g, 83% yield) as a white solid.

Step 7b: (4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone

To a 50-mL, round-bottomed flask fitted with a nitrogen inlet and magnetic stir bar was added (2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)(piperazin-1-yl)methanone dihydrochloride (3.0 g, 7.29 mmol), 1-hydroxycyclopropane-1-carboxylic acid (0.968 g, 9.48 mmol), 1-hydroxybenzotriazole hydrate (0.223 g, 1.459 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.818 g, 9.48 mmol), N-Methyl-2-pyrrolidinone (NMP) (15 mL), and 4-methylmorpholine (3.6 mL, 32.8 mmol). The mixture was stirred at rt and monitored for completion by LC/MS. Upon reaction completion (ca. 3 hours) the mixture was added to water (50 mL) and the resulting mixture stirred at rt overnight. The mixture was then filtered, and the solids washed with water (10 mL). The solids were dried on house vacuum (ca. 17 torr) to afford (4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (2.62 g, 85% yield) as a white solid containing 1.43 wt. % N-Methyl-2-pyrrolidinone.

The XRPD pattern of the crystalline Compound 1 Form C is depicted in FIG. 7, and the corresponding data is summarized below:

2 Theta d-spacing (Å) 9.6 9.3 10.1 8.8 10.9 8.1 13.5 6.6 13.9 6.4 14.3 6.2 15.5 5.7 15.9 5.6 16.3 5.4 16.8 5.3 17.5 5.1 18.1 4.9 18.4 4.8 18.9 4.7 19.6 4.5 22.2 4.0 24.2 3.7 24.9 3.6 26.6 3.3 27.9 3.2 30.5 2.9 31.1 2.9 35.5 2.5 38.7 2.3

As shown by TGA and DSC curves in FIG. 8, Form C showed a weight loss of 5.77% up to 100° C. and two endotherms at 101.1° C. and 224.0° C. before decomposition.

Form X

Compound 1 Form X was prepared by the following procedure:

To a 50-mL, round-bottomed flask fitted with a nitrogen inlet and magnetic stir bar was added (4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (5.0 g, 11.84 mmol) and acetonitrile (15 mL). To the mixture was added 1M HCl in water (15.00 mL, 15.00 mmol) with stirring. The homogeneous mixture was stirred at rt for 2 hours and then filtered through a fritted filter to remove insoluble material. The filtrate was cooled to 0° C. and 1M NaOH (15.00 mL, 15.00 mmol) was added at such a rate so as to maintain the temperature below 10° C. The mixture was stirred cold for 10 minutes and then allowed to warm to rt, during which time solids began to precipitate. The mixture was allowed to granulate overnight at rt. After overnight stirring (18 hours) the mixture was filtered, and the solids washed with water (15 mL). The material was dried on the filter under a nitrogen atmosphere followed by house vacuum (ca. 17 torr) to afford (4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (4.47 g, 89% yield) as a white solid.

The XRPD pattern of the crystalline Compound 1 Form X is depicted in FIG. 9, and the corresponding data is summarized below:

2 Theta d-spacing (Å) 7.2 12.2 8.1 11.0 8.5 10.4 12.7 7.0 13.1 6.7 13.5 6.6 14.4 6.1 14.9 6.0 15.3 5.8 15.6 5.7 16.1 5.5 16.9 5.2 17.1 5.2 17.8 5.0 18.5 4.8 19.1 4.7 21.0 4.2 21.4 4.2 23.3 3.8 24.2 3.7 25.5 3.5 27.1 3.3 27.9 3.2 29.1 3.1 29.8 3.0 30.6 2.9 31.2 2.9 32.3 2.8 33.6 2.7 35.9 2.5 38.1 2.4

As shown by TGA and DSC curves in FIG. 10, Form X showed a weight loss of 0.47% up to 150° C. and one endotherm at 232.9° C. (peak temperature) before decomposition. Form Z

Compound 1 Form Z was prepared by dissolving Compound 1 Mixture A in chloroform (CHCl₃), followed by slow evaporation of the chloroform.

The XRPD pattern of the crystalline Compound 1 Form Z is depicted in FIG. 11, along with a reference pattern of Compound 1 Mixture A.

As shown by the DSC curve in FIG. 12, Form Z showed one endothermic peak at 225.9° C. (onset temperature) and 229.6° C. (peak temperature) before decomposition.

Example 3—Stability Evaluation of Mixture A, Form B, and Form X

Slurry experiments with Mixture A were performed in two non-solvating solvents, EtOAc and ACN, at room temperature (RT) and 50° C. in order to evaluate the stability of Form B and Form X, which are two possible component forms of Mixture A. Mixture A was suspended in either EtOAc or ACN and stirred at either RT or 50° C., as indicated in Table 6, for 4 days. The solids collected were analyzed by XRPD to confirm the form change.

As summarized in Table 6 and FIG. 13, the solids from the slurries converted to Form B completely.

TABLE 6 Solvent Temperature Results EtOAc RT Form B ACN RT Form B EtOAc 50° C. Form B ACN 50° C. Form B

Example 4—Stability Evaluation of Form B and Form C

To evaluate the stability relationship between the hydrate Form C and the most stable anhydrate Form B, slurry competition experiments with Form B and Form C were conducted in different water activity (Aw) at RT. Form C was dissolved in three solvent mixtures (see Table 7) to get saturated solutions. Similar mass of Form B and Form C were added into the saturated solutions. The suspensions obtained were stirred at room temperature for 4 days and the solids collected were analyzed with XRPD.

As summarized in Table 7 and FIG. 14, the mixtures of Form B and Form C all converted completely to Form B.

TABLE 7 Solvent A_(w) Temp. Results H₂O/MeOH (85:915 v/v) 0.25 RT Form B H₂O/MeOH (225:775 v/v) 0.5 RT Form B H₂O/MeOH (494:506 v/v) 0.75 50° C. Form B

Example 5—Evaluation of Phase Stability and Kinetic Solubility of Form B in a Formulation

Kinetic solubility and phase stability of Form B was tested in a formulation (0.5% methyl cellulose (MC) and 0.5% Tween 80 in water). The sample was monitored by XRPD at 1, 2, 4 and 24 hours for phase stability. As shown in FIG. 15, no phase transformation was observed after 24 h. Kinetic solubility of Form B was measured in the same formulation at time points of 1, 2, 4 and 24 hour (Table 8). The supernatant was obtained by filtration and the concentration was measured by HPLC. The result showed that the solubility remained stable during 24 hours at RT. No significant degradation was observed from the solubility sample.

As summarized in Table 8 and FIG. 15, Form B showed 0.06 mg/mL solubility in 24 hours in the formulation, as well as no form change or significant degradation in the vehicle.

TABLE 8 Solubility Purity Time Point (mg/mL) (% area at 240 nm) 1 h 0.062 97.8 2 h 0.062 97.8 4 h 0.063 97.7 24 h  0.060 97.7

Example 6—Formulations of Compound 1 Form B

Compound 1 Form B can be formulated into a form (e.g., a capsule or unit dosage form) for oral use.

Compound 1 Form B was incorporated into a unit dosage form by encapsulation in capsules comprising hydroxypropyl methylcellulose (HPMC). The composition of the capsule comprising HPMC was selected to provide suitable resistance to hydroscopic active compounds, with asuitable resistance to moisture permeation, not prone to moisture variability (e.g., about 13-16% moisture content in a hard gelatin capsule shell). The oral unit dosage form can be a capsule containing a dose strength of 0.3 mg, 3 mg, or 9 mg.

Compound 1 Form B was formulated into capsules containing 1% w/v of Compound 1 Form B with other excipients in a 1 mL shell vial, as summarized in Table 9.

TABLE 9 Formula- Formula- Formula- tion 1 tion 2 tion 3 Component Function (rel. volume) (rel. volume) (rel. volume) Capryol 90 Polymer 0.5 0.5 — Capmul MCM Polymer 0.5 — 0.5 PEG 4000 Polymer — 0.5 0.5

Compound 1 Form B was formulated via dry blending into capsules in size 4 hard gelatin capsules as summarized in Table 10.

TABLE 10 Formula- Formula- Formula- tion 4 tion 5 tion 6 Component Function (% w/w) (% w/w) (% w/w) Micronized Active 11.25 11.25  11.25 Compound 1 Form B Parteck M100 Filler 38.88 38.88  38.88 (Mannitol) Avicel PH 101 Filler 38.87 38.87  38.87 Sodium Surfactant 5.00 — — dodecyl sulfate Poloxamer 188 Surfactant — 5.00 — Poloxamer 407 Surfactant — — 5.00 Ac-Di-Sol Disintegrant 5.00 5.00 5.00 Mg Stearate Lubricant 1.00 1.00 1.00

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims. 

What is claimed is:
 1. A solid form of Compound 1 free base:

wherein the solid form is selected from the group consisting of Mixture A, Form B, Form C, Form X, and Form Z.
 2. The solid form of claim 1, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3.
 3. The solid form of claim 1, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 15.4, 19.6, and 22.3 and not having a diffraction at angle (2 theta±0.2) of 24.2.
 4. The solid form of claim 1, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 12.6, 13.9, 15.4, 16.4, 19.6, 20.2, 22.3, 23.4, 23.8, and 25.3.
 5. The solid form of claim 3, wherein the solid form is Form B and is characterized by a DSC endotherm having an endotherm at about 226° C.
 6. The solid form of claim 3, wherein the solid form is Form B and is characterized by a TGA with a weight loss of about 0.5% between 21° C. and 100° C.
 7. The solid form of claim 3, wherein the solid form is Form B and is characterized by a DVS of about 0.5% water by weight below 95% relative humidity.
 8. The solid form of claim 1, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 15.4, 19.6, 22.3, and 26.6.
 9. The solid form of claim 1, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 15.4, 19.6, 22.3, 24.2, and 26.6.
 10. The solid form of claim 1, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 7.2, 8.5, 14.9, 16.1, and 17.8.
 11. A composition comprising Compound 1 free base Mixture A:

wherein Mixture A is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3.
 12. The composition of claim 11, wherein Mixture A is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, 21.0, and 22.3.
 13. A pharmaceutical composition comprising a solid form of Compound 1 free base:

and a pharmaceutically acceptable carrier, wherein the solid form of Compound 1 is Form B and is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3.
 14. The pharmaceutical composition of claim 13, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 15.4, 19.6, and 22.3 and not having a diffraction at angle (2 theta±0.2) of 24.2.
 15. The pharmaceutical composition of claim 13, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 15.4, 19.6, and 22.3 and not having a diffraction at angle (2 theta±0.2) of 24.2.
 16. The pharmaceutical composition of claim 13, wherein the solid form is characterized by an XRPD pattern having diffractions at angles (2 theta±0.2) of 9.6, 10.1, 12.6, 13.9, 15.4, 16.4, 19.6, 20.2, 22.3, 23.4, 23.8, and 25.3.
 17. The pharmaceutical composition of any one of claim 13, wherein the pharmaceutical composition is substantially free of Solid Form X.
 18. The pharmaceutical composition of any one of claim 13, wherein the pharmaceutical composition is substantially free of Solid Forms C, X, and Z.
 19. A solid form of Compound 1:

wherein the solid form is the form that would be obtained by a process comprising: suspending at least one of Mixture A, Form C, and Form X of Compound 1 in a solvent selected from a group consisting of ethyl acetate (EtOAc), acetonitrile (ACN), heptane, isopropyl alcohol (IPA), and ethanol (EtOH) to provide a slurry; and maintaining the slurry for a period of at least 5 hours to afford the solid form of Compound
 1. 20. The solid form of claim 19, wherein the slurry is heated to a temperature from about 50° C. to about 100° C. after suspension in the solvent.
 21. The solid form of claim 19, further comprising isolating the solid form of Compound 1 from the slurry. 